Chronic impact of traumatic brain injury on outcome and quality of life: a narrative review

Neuronal circuits and functions depend on white matter integrity [9]. Seminal neuropathological studies by Adams and colleagues have documented the distribution of axonal pathology in a large series of TBI cases and have introduced the concept of “diffuse axonal injury” [10, 11]. Shear-tensile forces due to trauma may cause a disruption of the axonal cytoskeleton and impair axonal transport. Additional neurochemical changes, such as intracellular calcium overload, may further damage the axons. Thus, TBI affects structural brain networks progressively, from focal axon alteration to delayed axonal disconnection [12, 13].

The functional and structural connectivity in patients can now be investigated by resting-state functional MRI and advanced diffusion imaging (Fig. 3), respectively, documenting axonal damage over a wide range of injury severities [8, 14, 15].

Studies indicate that even apparently intact axons with disrupted physiology may contribute greatly to clinical dysfunction in mild TBI. White matter abnormalities on advanced neuroimaging studies are evident in many patients in whom CT scans are normal and are strong predictors of long-term consequences [2, 9, 16, 17]. Serum markers of axonal injury are emerging (i.e., “SNTF”, a proteolytic fragment of alpha-II spectrin) that may assist in monitoring of neuropathology progression [18].

TBI is a risk factor for delayed neurodegeneration and dementia, including Alzheimer’s disease and chronic traumatic encephalopathy [19, 20]. Several mechanisms may be implicated, including axonal injury, neuronal loss, persistent inflammation, and prolonged blood–brain barrier disruption [21‐24]. However, the neuropathological link that is receiving most attention is the accumulation of amyloid-β peptides and aberrant microtubule-associated protein tau, two common features in Alzheimer disease. Tau pathology has been shown to occur in rodent models of TBI within 2 weeks of injury [25‐27]. Recent evidence indicates that a focal brain trauma in mice leads to persistent tau pathology which disrupts axonal microtubule networks, propagates to remote regions in the brain, and is associated with brain dysfunction [28].

The inflammatory response in TBI includes local cerebral production of cytokines and chemokines, endothelial activation, microglial activation, and migration of systemic neutrophils, lymphocytes, and monocytes into the injured brain. In experimental TBI, microglial cells readily activate [29] and remain chronically activated for at least one year after injury [30], spreading form the site of injury to remote regions in the brain. Clinical data from TBI brain autopsies and from positron emission tomography of TBI patients identify chronic microglia activation up to several years after injury and document a close association between neuropathology and inflammation in space and time [31, 32]. Experimental studies show that aspecific suppression of the inflammatory response may protect the injured tissue early on but harm the brain at chronic stages [33], suggesting that therapeutic strategies should aim at modulation, rather than inhibition, of the inflammatory response.

In addition to toxic processes, TBI also induces neurorestorative events that include neurogenesis, gliogenesis, angiogenesis, synaptic plasticity, and axonal sprouting. These processes are stimulated by endogenous growth-related factors and may persist for weeks to months, contributing to recovery after TBI.

The adult brain retains neurogenic zones with neural stem cells that can differentiate into functional neurons [34, 35]. Several laboratories have reported an increased proliferative response in the hippocampus beginning as early as 2 days post-injury [36], with a peak in the first weeks after injury [37]. The proliferation in the dentate gyrus is age-dependent, with the juvenile brain showing a greater potential [36]. Newly generated neuroblasts [38] have been shown to migrate toward the site of injury [39] and to participate in cognitive recovery [40, 41]. Next to neurogenesis, axonal sprouting and synaptogenesis from surviving neurons may play a role in spontaneous motor recovery after TBI [42, 43]. However, all these spontaneous brain restorative processes are short-lived [44‐46].

TBI patients have a higher mortality rate than controls matched for age and sex. Behavioral problems, impulsivity, suicide, motor accidents, etc. are more common in young survivors, while in cases older than 45 years medical problems such as pneumonia, sepsis, and neurodegenerative diseases are associated with early deaths. In an American study the risk of dying was 2.2 times more than controls considering moderate to severe TBI who received inpatient rehabilitation, with an average reduction of life expectancy of 6.6 years [59]. The data were much worse for individuals who were unable to follow commands on admission to rehabilitation: they were 6.9 times more likely to die, with an average life expectancy reduction of 12.2 years.

The vegetative state (or “unresponsive wakefulness syndrome”) is a complex neurological condition in which patients appear to be awake but show no sign of awareness of themselves or their environment [60]. This condition may be transient, preceding further recovery, or persist. If repeated accurate assessments confirm unresponsiveness 1 year after injury, a persistent vegetative state is diagnosed [59]. A high rate of misdiagnosis is reported because of the barriers to communication from the patient and the environment, so that patients with minimal, but present, responses (minimally conscious state) are confused with cases without responsiveness. These responses can be detected by complementing clinical evaluation with electrophysiology [61] and sophisticated imaging techniques [62].

Motor and sensory deficits may persist as a consequence of specific traumatic damage to the underlying nervous structures. In the most severe cases, additional damage due to prolonged immobilization during hospital care, such as peri-articular calcification, may worsen recovery. Bladder and sphincter control may be impaired. All these physical disabilities may cause significant handicap and limit the return to a normal and productive life.

TBI has been identified as a risk factor for dementia but this topic is still debated. A large retrospective cohort (more than 50,000 mild, moderate, and severe TBI cases) identified 4361 (8.4 %) cases who developed dementia. In a stratified adjusted analysis, moderate to severe TBI was associated with increased risk of dementia across all ages, whereas mild TBI appeared to be a more important risk factor only in older cases (65 years or older) [63].

Individual hormonal deficiencies after adult TBI are greatly variable in different reported studies. Chronic dysfunction of the pituitary axis is observed in approximately 35 % of individuals who sustain a moderate-to-severe TBI. The most common deficiency is that of growth hormone (GH), followed by gonadotropin, cortisol, and thyroid [64]. GH replacement provides clinically relevant, long-term QoL benefits in TBI patients with severe hypopituitarism [65]. When hormone deficits are not recognized and managed appropriately, they may profoundly affect both the results of the rehabilitative efforts and the final outcome of the subjects.

TBI causes deficits of attention, memory, information processing speed, and executive functioning. High-level cognitive functions depend on well functioning distributed brain networks and on finely regulated neurotransmitter systems [8, 15], which may be disrupted by injury. When a group of moderate to severe TBI cases was extensively studied through comprehensive neuropsychological screening, deficits in sustained attention, paired associate learning, and reaction time have been clearly shown [66].

The relationship between TBI severity and neuropsychological deficits has been studied up to 10 years after injury [67]. Fifty per cent of mild cases recovered complete cognitive competency, while an additional 20 % required “some help”. On the other end of the spectrum, only 30 % of the more severe cases fully recovered [68]. More encouraging data on mild injuries recovery are reported in a recent systematic review [5].

White matter damage in definite locations, as demonstrated by advanced imaging techniques, seems to be associated with specific disorders: for instance, lesions to the fornices are correlated with associative learning and memory deficits; frontal lobe lesions are strictly linked with executive function impairment [15]. Grey matter lesions (especially in the orbitofrontal and insular cortices and in the caudate) seem associated with impulsivity; impairment of decision making, with longer deliberation times, also seems to be associated with a number of anatomical lesions [8].

As already mentioned, TBI is increasingly affecting an aging population in several countries; the neural loss that accompanies normal ageing might combine or interact with the brain damage caused by a TBI and worsen patients’ cognitive and social abilities [69, 70].

Psychiatric disorders are common following TBI and include depression, anxiety, and psychosis, as well as other maladaptive behaviors and personality changes. A recent meta-analysis shows that TBI increases the incidence of psychiatric disorders, with depression and bipolar disorders having higher odds ratios, 2.1 and 1.85, respectively. Psychiatric symptoms may be temporary, limited to the first weeks after injury, or persistent. They may limit participation in rehabilitation and functional independence in the community. Long-term psychiatric disorders are associated with greater risk for substance abuse [71].

The incidence of seizures after TBI is variable, depending on the mechanism, the location, and the extent of brain damage and on appropriate treatment. Penetrating injuries are very often the cause of seizures, which may affect up to 50 % of patients. In closed TBI, the incidence of late seizures is lower but it may vary between 9 and 42 % in untreated patients [72]. Other sources indicate an incidence of 25–30 % after severe TBI and 5–10 % after mild to moderate injury [73]. There is low-quality evidence that early treatment with antiepileptic drugs reduces the risk of early post-traumatic seizures and no evidence to support a reduction in the risk of late seizures [74].

The combination of physical and functional deficits discussed translates into a high rate of un-employment in survivors of TBI. Patients recovering from severe TBI are sometimes offered a sheltered working environment, while return to previous work positions is rare. In a USA series 73 % of cases with mild initial injury return to previous jobs; this proportion falls to 49 % for severe patients [68]. Even patients of working age with apparently favorable outcomes have difficulties in restarting their jobs: in a group studied in Norway 10 years after injury, the rate of employment was 58 % [67].

Brain injury can directly and indirectly affect important aspects related to sexuality and sexual function. Physical (for instance pituitary dysfunction) and psychological components (such as depression) may both result in impaired sexual activities. When sexual function has been studied 1 year after TBI with self-reports and structured interviews, significant disturbances were detected [75]; 29 % of participants reported dissatisfaction with sexual functioning, with a greater percentage of men reporting dissatisfaction.

Sexual issues and sexual needs are rarely discussed and managed during the rehabilitation phase after TBI [76].

The combination of physical, cognitive, and emotional impairments creates a major obstacle for re-entry into the community. Decreased social contact, depression, and loneliness combined with reduced financial resources, unemployment, and physical disabilities may severely disrupt previous social networks and make social and leisure activities impossible [77].

When several parameters (neuropsychological functioning, emotional status, functional status, employment, and perceived QoL) were assessed in 201 patients with moderate or severe TBI up to 3–5 years after injury, recovery to pre-injury levels ranged from 65 % of cases with regard to personal care to approximately 40 % with regard to cognitive competency, major activities, and leisure and recreation [68]. These figures were related to initial TBI severity.

Other series measuring QoL and comparing it with matched comparators confirm these findings: TBI cases experienced worse general health, elevated probabilities of depression, social isolation, and worse labor-force participation rates. The most affected areas were social function, emotions, and mental health [78]. Patients typically report “somewhat lower life satisfaction and affect” as a consequence of TBI [79]. QoL is consistently worse in older patients, as documented after the evacuation of subdural hematomas [80].